Supramolecular nanoagent as a dual-blocked thermoresistance inhibitor for effective mild-temperature photothermal therapy

Abstract

Mild-temperature (<45 °C) photothermal therapy (PTT) is a promising approach to kill cancer cells by inhibiting the expression of heat shock proteins (HSPs) related to thermoresistance, a method commonly applied in most mild-temperature PTT studies. Regrettably, thermoresistance cannot be fully suppressed solely by inhibiting HSPs. Under normal conditions, heat shock factor 1 (HSF-1) remains inactive and forms a complex with HSPs. However, HSF-1 can dissociate from the complex and be activated, leading to the continuous production of significant amounts of HSPs, which in turn triggers thermoresistance upon heating. Therefore, simultaneously inhibiting both HSPs and HSF-1 activities presents a more effective strategy for developing mild-temperature PTT than only inhibiting HSPs. In this work, we focus on the complete blocking of thermoresistance to create a novel supramolecular nanoagent, IQ@NPs, for mild-temperature PTT. IQ@NPs demonstrated excellent drug release, tumor accumulation, and photothermal conversion, resulting in a rapid increase in the temperature of tumor sites to 42.9 °C within 5 min of irradiation. Western blotting revealed that IQ@NPs significantly inhibited the expression of HSPs (HSP90) and HSF-1. After 15 d treatment, tumor growth was significantly suppressed by IQ@NPs through effective mild-temperature PTT. Furthermore, IQ@NPs exhibited satisfactory safety and minimal side effects. This study represents a progressive advancement in mild-temperature PTT.